The aim of this project is to gain a greater understanding of the psychobiology of schizophrenia and to develop improved strategies for the treatment of this illness. Clinical research for this project is carried out on the 4-East Nursing Unit of the Clinical Center. Patients with DSM-III diagnosed schizophrenia are studied during a several month research period during which time they are treated under double-blind conditions with neuroleptic and placebo medications. An important goal of this project has been the investigation of the mechanism of action of neuroleptic drugs and a profile of which symptoms are most responsive to drug treatment. We have observed that neuroleptic-induced, time-dependent decreases in levels of plasma homovanillic acid (HVA) (a major dopamine metabolite) correlate with antipsychotic drug response for a group of schizophrenic patients. Further, we have observed that the degree of reduction of plasma HVA is correlated with the degree of reduction of psychotic symptoms in individual patients. These data suggest that slow to develop neuroleptic effects on dopamine release are related to the clinical effects of neuroleptic treatment. In studies of symptomatology of schizophrenic patients we have demonstrated that both positive and negative symptoms are sensitive to neuroleptic treatment. Results from 24-hour studies in which plasma HVA is sampled hourly have supported our observation of neuroleptic-induced decrease in levels of plasma HVA and have also established a marked diurnal rhythm in plasma HVA in normal controls. The possibility of disordered plasma HVA rhythms in schizophrenic patients is being investigated. We are currently investigating the effects of the novel benzodiazepine, alprazolam, as an additive pharmacologic treatment to neuroleptics in schizophrenic patients.